Research in my laboratory focuses on the responses of mammalian cells to DNA double-strand breaks (DSBs). Cellular responses to DSBs are of paramount importance in the field of cancer biology because 1) DNA damage causes cancer, 2) DNA damage is used to treat cancer, and 3) DNA damage underlies most of the side effects of cancer therapy. Our research, therefore, aims to understand some of the mechanisms of DSB recognition, signaling, and repair in mammalian cells, collectively known as the DNA damage response (DDR). Below is a summary of the three key projects that are ongoing in the lab:
1) According to the current paradigm of DNA damage signaling, ATM is activated directly by DSBs while ATR is activated after the resection of DSBs into ssDNA in an ATM/Mre11 dependent manner. Our current research revises this existing paradigm by demonstrating that checkpoint signaling proteins are rapidly phosphorylated independently by ATR in an Exo1-dependent manner while proteins involved in chromatin remodeling are also phosphorylated by DNA-PKcs. Ongoing research aims to better understand and redefine the contributions of the PIKK family of kinases - ATM, ATR, and DNA-PKcs - to DDR.
2) Glioblastoma multiforme (GBM) are lethal brain tumors that are highly resistant to IR. We find that expression of constitutively active EGFRvIII (a key GBM-specific mutation) in astrocytes or neural stem cells and in orthotopic tumor models confers radioresistance by promoting the rapid repair of DSBs. Our current research aims to advance this novel concept in cancer biology, i.e., elevated receptor tyrosine kinase (RTK) signaling in cancer cells bolsters DDR by hyper-activating key kinases responding to DSBs.
3) Under the auspices of a grant from NASA, we are studying both early and late cellular responses to complex DNA damage inflicted by HZE (High-Z, High-Energy) particles that are the most deleterious component of Galactic Cosmic Rays. These studies are also pertinent from a therapeutic standpoint due to the increasing use of protons and carbon ions in targeted cancer therapy. We find that mammalian cells are unable to repair a significant portion of DSBs induced by HZE particles and, as a consequence, these ions are highly tumorigenic compared to gamma rays. We are currently examining the genomic and gene expression changes underlying HZE-induced carcinogenesis.
RESEARCH INTERESTS
Recognition, signaling, and repair of DNA double-strand breaks
Distinct roles of ATM, ATR, and DNA-PKcs in DNA damage signaling
Genetic basis of radioresistance in glioblastomas and strategies for radiosensitisation
Responses of mammalian cells to Galactic Cosmic Rays
RECENT PUBLICATIONS
N Tomimatsu, B Mukherjee, S Burma, "Distinct roles of ATR and DNA-PKcs in triggering DNA damage responses in ATM-deficient cells" EMBO Reports, 2009
J Li, DP Sejas, S Burma, DJ Chen, Q Pang, "Nucleophosmin suppresses oncogene-induced apoptosis and senescence and enhances oncogenic cooperation in cells with genomic instability." Carcinogenesis, 28(6):1163-70, June 2007
Mukherjee B, Kessinger C, Kobayashi J, Chen BP, Chen DJ, Chatterjee A, Burma S, "DNA-PK phosphorylates histone H2AX during apoptotic DNA fragmentation in mammalian cells." DNA Repair, 5(5):575-590, May 2006
Chen BP, Chan DW, Kobayashi J, Burma S, Asaithamby A, Morotomi-Yano K, Botvinick E, Qin J, Chen DJ, "Cell cycle dependence of DNA-PK phosphorylation in response to DNA double-strand breaks." J Biol Chem., 280(15):14709-15, April 2005
Silvera D, Koloteva-Levine N, Burma S, Elroy-Stein O, "Effect of Ku proteins on IRES-mediated translation." Biol Cell, 98(6):353-61, June 2006
SIGNIFICANT PUBLICATIONS
Burma S, Chen B, Chen DJ, "Role of non-homologous end joining (NHEJ) in maintaining genomic integrity." DNA Repair, 5(9-10):1042-48, September 2006
Burma S, Chen DJ, "Role of DNA-PK in the cellular response to DNA double-strand breaks." DNA Repair, 3(8-9):909-18, August 2004
Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ, "ATM phosphorylates histone H2AX in response to DNA double-strand breaks." J Biol Chem., 276(45):42462-7, November 2001
Burma S, Kurimasa A, Xie G, Taya Y, Araki R, Abe M, Crissman HA, Ouyang H, Li GC, Chen DJ., "DNA-dependent protein kinase-independent activation of p53 in response to DNA damage." J Biol Chem., 274(24):17139-43, June 1999
Woo RA, Jack MT, Xu Y, Burma S, Chen DJ, Lee PW, "DNA damage-induced apoptosis requires the DNA-dependent protein kinase, and is mediated by the latent population of p53." EMBO J., 21(12):3000-8, June 2002
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